Atlas of Cardiomyopathy Associated <i>DES</i> (Desmin) Mutations: Functional Insights Into the Critical 1B Domain

The atlas of cardiomyopathy-associated desmin mutations represents a significant step toward improving the clinical interpretation of <i>DES</i> variants associated with cardiomyopathies. Our data provide robust evidence that 4 variants of previously unknown significance listed in the ClinVar database warrant reclassification as likely pathogenic mutations based on their molecular effects. Specifically, we demonstrated that proline insertions-particularly at positions where hydrophobic amino acids contribute to the intermolecular interactions between alpha helices-lead to desmin filament assembly defects. These findings not only enhance our understanding of desmin-related cardiomyopathies but also offer a valuable resource for cardiologists and genetic counselors in guiding diagnosis, risk stratification, and patient counseling.